High Response Rate in Heavily Treated Multiple Myeloma With Novel Drug Combination

A novel combination for relapsed/refractory multiple myeloma produced responses in about 80% of a heavily treated population, albeit with a high incidence of hematologic toxicity and infections.

The 94-patient cohort had an overall response rate (ORR) of 78% across a range of doses of talquetamab (Talvey) and teclistamab (Tecvayli), including 80% of patients treated with the recommended phase II dose. Grade 3/4 adverse events (AEs) occurred in 96% of patients and grade 3/4 infections in 64%.

Among responding patients, the likelihood of persistence at 18 months was 86%, reported Yael C. Cohen, MD, of Tel Aviv Sourasky Medical Center in Israel, and co-authors in the New England Journal of Medicine.

“In this study, talquetamab plus teclistamab had a similar safety profile to each agent as monotherapy, although the observed incidence of grade 3 or 4 infections was higher with the combination than with talquetamab or teclistamab as monotherapies,” the authors stated in their conclusions. “Responses were observed across dose levels and were particularly deep and durable with the recommended phase II regimen.”

“On the basis of these results, this dual-targeting, off-the-shelf combination therapy warrants further investigation in patients with relapsed or refractory multiple myeloma.”

Both drugs have FDA-approved indications in relapsed/refractory myeloma, teclistamab in 2022 (after failure of four prior therapies) and talquetamab a year later (also after four prior therapies). Each of the agents represents a first-in-class treatment strategy for myeloma.

The bispecific antibody teclistamab redirects T cells through B-cell maturation antigen and CD3 to activate the immune system against cancer. Support for the agent’s approval came from the MajesTEC-1 trial, which showed an ORR of 65% in a 40-patient subgroup who received the phase II dose. Updated results after longer follow-up showed a 63% ORR and median response duration of 18.4 months.

Talquetamab, also a bi-specific T-cell engager, targets CD3 and GPRC5D. In the 288-patient, phase I/II MonumenTAL-1 trial, more than 70% of the patients, who had received three or more prior lines of therapy, responded to either of two doses of talquetamab. Even patients previously treated with a bispecific antibody or CAR T-cell therapy had response rates as high as 70%.

Cohen and colleagues hypothesized that “dual antigen targeting with talquetamab plus teclistamab may further enhance treatment potency, maximize tumor eradication in heterogeneous cell populations, prevent resistance due to tumor antigen escape, and increase durability of response.”

To test the hypothesis, investigators in Israel, Canada, South Korea, and Spain conducted a still-ongoing phase Ib/II nonrandomized, open-label trial of the two drugs. Eligible patients had prior exposure to a proteasome inhibitor, immunomodulator, and anti-CD38 monoclonal antibody. Patients with extramedullary disease with at least one non-irradiated, bone-independent lesion and those with nonsecretory or oligosecretory extramedullary disease were eligible.

The trial investigated five escalating dose levels of the drugs, administered over 28-day cycles. The primary endpoint of phase I was dose-limiting toxicity (DLT). Secondary endpoints included ORR, duration of response, time to response, pharmacokinetics, pharmacodynamics, and immunogenicity.

Three patients had DLTs across the dose ranges evaluated (one case each of grade 3 oral herpes, grade 3 elevated liver enzymes, and grade 4 thrombocytopenia). Hematologic toxicities accounted for 80% of the grade 3/4 AEs. The most common any-grade AEs were cytokine release syndrome (79%), neutropenia (73%), taste changes (65%), and nonrash skin events (61%).

More than 90% of patients had treatment delays or dose modifications because of AEs, primarily infections. AEs led to discontinuation of one or both drugs by 15 patients, attributed to study drug in seven cases. Fourteen patients died of causes related to AEs, including pneumonia, multiple types of infection, sepsis, cardiac arrest, leptomeningeal myelomatosis, and respiratory failure. Six grade 5 (fatal) AEs were attributed to a study drug.

Among patients treated with the phase II dose combination, objective responses occurred in 35 of 44 (80%). Median time to response was 1.4 months. The ORR included complete response or better in 23 (52%) and very good partial response or better in 34 (77%). Response rates in subgroups of interest included seven of eight patients with International Staging System III myeloma, six of eight with high-risk cytogenetics, and 11 of 18 with extramedullary disease.

Across the range of doses, 73 of 94 patients achieved objective responses (median time to response 1.8 months). A total of 70 patients (74%) had a very good partial response or better and 45 (48%) had complete response or better. The response rate was numerically higher among patients without extramedullary disease (88% vs 59% for those with extramedullary disease).

The likelihood of ongoing response at 12 and 18 months with the recommended phase II dose was 91% and 86%, respectively. Across the range of doses, the 12- and 18-month response rates were 86% and 77%. The estimated progression-free survival at 12 and 18 months was 74% and 70%, respectively, with the phase II dose, and 71% and 62% across all doses.

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